Researchers from the National Institutes of Health
have discovered the critical sequence of events by which
insulin stimulates the entry of glucose into fat cells.

The study, appearing in the May 9 Journal of Cell Biology,
was conducted by researchers from the National Institute
of Child Health and Human Development and the National
Institute of Diabetes and Digestive and Kidney Diseases.

“This finding provides useful information for understanding
disorders in which cells have difficulty using insulin,
such as insulin resistance and type 2 diabetes,” said
NICHD Director Duane Alexander, M.D.

Glucose, a simple sugar, is a nutrient that cells need
to survive, explained the study’s corresponding author,
Joshua Zimmerberg, M.D., Ph.D., chief of NICHD’s Laboratory
of Cellular and Molecular Biophysics. Glucose is ferried
through the cell’s outer covering, or membrane, by a
family of molecules known as glucose transporters. In
the study, the researchers discovered how glucose transporter
4 (GLUT 4) carried insulin into fat cells.

Previously, scientists had learned that, within the
cell, GLUT 4 is contained in the membrane of tiny sacs
known as vesicles. Another author of the current study,
Samuel Cushman, Ph.D., of NIDDK’s Diabetes Branch, had
found in earlier studies that GLUT 4 was transferred
from the vesicles within the cell to the cell membrane,
when the vesicles combined, or fused with, the membrane.
Researchers had been unable to determine, however, where
in the cell the vesicles were stored and how insulin
stimulated them to fuse with the cell membrane.

In the current study, the NIH researchers observed
fat cells taken from mice and learned that the GLUT
4 vesicles are highly active. They discovered that,
although a few vesicles are scattered throughout the
cell, the majority circulate just under the cell’s surface.
The vesicles travel along a railroad track-like network
of molecules known as microtubules. When insulin binds
to the cell’s outer surface, those vesicles immediately
stop moving, tether to the cell’s inner surface, then
fuse with the cell membrane. GLUT 4, contained in the
vesicles’ membrane, then enters the cell membrane, where
it ferries glucose into the cell.

The researchers made their observations using a technique
known as total internal reflector florescent microscopy.
The technique consists of aiming a laser beam at an
angle at the glass cover slip beneath the microscope,
explained the last author of the paper, Vadim A. Frolov,
Ph.D., of NICHD’s Laboratory of Cellular and Molecular
Biophysics and the Russian Academy of Science in Moscow.
The light bounces off the cover slip, away from the
microscope’s lens. However, residual energy from the
light passes through the cover slip, to the cell beneath,
illuminating the area just below the cell’s surface
while leaving the inside of the cell dark.

“When we started the experiment, we thought that the
vesicles would be stationary,” Dr. Zimmerberg said. “The
vesicles looked like comets streaking by.”

Dr. Zimmerberg added that studying the chemical steps
of the process in which the vesicles fuse with the cell
membrane might yield a new drug to treat insulin-related
disorders. He added that each step in the process might
provide the basis for a treatment: when the vesicles
first stop moving, when they tether to the inside of
the cell’s membrane, and when they fuse with the membrane.

Next, the researchers plan to observe cells taken from
mice having conditions resembling human disorders of
insulin metabolism. Eventually, the researchers hope
to obtain cell samples from volunteers who have been
diagnosed with type 2 diabetes and insulin resistance.

The NICHD is part of the National Institutes of
Health (NIH), the biomedical research arm of the federal
government. NIH is an agency of the U.S. Department
of Health and Human Services. The NICHD sponsors research
on development, before and after birth; maternal,
child, and family health; reproductive biology and
population issues; and medical rehabilitation.